In the last several years, a sense of urgency and a renewed interest in the study of radionuclide chemistry and biology have emerged, as threats of nuclear terrorism have become more plausible, and the risk of environmental contamination and human exposure to radioisotopes consequently increased. The only practical therapy to reduce the dramatic health consequences of internal actinide/lanthanide contamination is treatment with chelating agents that form excretable complexes, although fission product lanthanides and the actinides are among the most intractable radionuclides to decorporate. While diethylenetriaminepentaacetic acid (DTPA) has been the standard therapy for actinide/lanthanide decorporation for several decades, it has limited efficacy and is not yet orally available. Hydroxypyridonate sequestering agents developed in our laboratory are selective and have a high affinity for plutonium(IV), americium(III), a number of other actinide ions, and lanthanide ions. Extensive efficacy studies in mice have been published and a limited number of tests have been performed in dogs and baboons, establishing that two of the designed agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2- HOPO), are up to 30 times more effective than DTPA and, unlike DTPA, are orally active. In addition, recent methods for large-scale synthesis, preclinical toxicity studies in rats and in vitro cytotoxicity studies using human cells have demonstrated that the selected chelators exhibit low toxicity and hold promise as non-toxic orally available actinide/lanthanide decorporation agents. The objective of this two-year project application is to sustain a large-scale interdisciplinary research program that will carry forward the pre-clinical development of both selected therapeutic actinide/lanthanide decorporation agents for emergency use and to enable the establishment of a viable infrastructure dedicated to the study and understanding of actinide and lanthanide chelation in biological systems. Compound characterization, actinide removal efficacy studies in mice and dogs, pre-clinical safety studies in rats and dogs and permeability assessment using rat intestinal tissues will be performed in collaboration with scientists from the Lawrence Berkeley National Laboratory, SRI International, and the Lovelace Respiratory Research Institute (LRRI). Finally, early input from the FDA will be obtained for our ligand development plan to enable the timely and successful filing of an IND application. As underlined by the National Institute of Allergy and Infectious Diseases (NIAID) Radiation Countermeasures Program, the development of radionuclide decorporation agents responds to the urgent need to protect the general population from the consequences of a large-scale exposure to radionuclides. In the event of a radiological/nuclear terrorist event, prospective decorporation treatments must be suitable to treat a large population that could be exposed to a variety of agents with a potentially high number of casualties. This project focuses on meeting the criteria listed by NIAID for the pre-clinical development of actinide and lanthanide decorporation agents, which include (i) chelation and elimination of a range of actinides/lanthanides, (ii) oral administration, (iii) effectiveness when administration is delayed, and (iv) safety for all potential populations.